The protocol was approved by the Mount Sinai School of Medicine Institutional Review Board, and voluntary informed consent was obtained from all participants. Six unrelated AJ patients with classic MSUD (individuals 2–6 and 9), one patient with intermediate MSUD (individual 1), and the parents of one classic patient (individuals 7 and 8) participated in this study. Here we report the carrier frequency of a common AJ mutation, R183P, and the identification of two novel mutations. In our clinic, we noted that a disproportionate percentage (∼30%) of families with MSUD were of Ashkenazi Jewish (AJ) heritage. However, a founder effect in the Pennsylvania Mennonite population has led to an increased incidence (1/176) in this population (Marshall and DiGeorge 1981). MSUD has been described in all ethnic groups and has an estimated worldwide frequency of 1/185,000 (Naylor 1980). Despite early diagnosis and adequate care, episodes of life-threatening metabolic decompensation occur during periods of stress or infection and are associated with significant morbidity and mortality (Riviello et al. 1991), emphasizing the importance of newborn-screening programs. However, a significant proportion of treated individuals have impaired intellectual development or neurological complications, particularly as a result of delayed diagnosis (Kaplan et al. Patients with MSUD can be effectively managed with dietary restriction of the branched-chain amino acids and maintenance of strict biochemical control (Snyderman et al. Mutations in any of the E1 or E2 components can result in classic, intermediate, or intermittent MSUD, although they are more frequent in E1α and E1β than in E2 (Nellis and Danner 2001). ![]() The less-common forms are the later-onset intermediate type, an episodic intermittent type, an intermediate-like thiamin-responsive type, and E3 deficiency with lactic acidosis. Classic MSUD, the most common clinical presentation, manifests during the newborn period and can result in severe neurological complications and death. ![]() Because the E3 subunit is shared with the pyruvate and α-ketoglutarate dehydrogenase complexes, decreased activity of this component results in deficiencies of all three enzymes.įive clinical MSUD phenotypes have been described, which differ in their presentation and severity. The E1 subunit exists as a heterotetramer composed of two E1α and two E1β subunits. Two regulatory subunits, BCKAD kinase and BCKAD phosphatase, are also associated with the E2 core (Damuni et al. BCKAD exists as a multienzyme complex composed of a multimeric core of dihydrolipoyl acyltransferase (E2), to which are bound multiple BCKAD decarboxylase (E1) and dihydrolipoamide dehydrogenase (E3) subunits (Pettit et al. The enzymatic defect, transmitted in an autosomal recessive manner, results in an inability to catabolize leucine, isoleucine, and valine. 1954), maple syrup urine disease (MSUD) (types Ia, Ib ), and II ), is an inborn error of metabolism, resulting from the defective activity of branched-chain α-ketoacid dehydrogenase (BCKAD) (Chuang and Shih 2000). Originally described by Menkes in 1954, as a rapidly fatal neurodegenerative disease (Menkes et al. ![]() These findings suggested that a limited number of mutations might underlie MSUD in the AJ population, potentially facilitating prenatal diagnosis and carrier detection of MSUD in this group. ![]() Large-scale population screening of AJ individuals for R183P, the mutation present in six of seven patients, revealed that the carrier frequency of the mutant allele was ∼1/113 the patient not carrying R183P had a previously described homozygous mutation in the gene encoding the E2 subunit. The locations of the affected residues in the crystal structure of the E1β subunit suggested possible mechanisms for the deleterious effects of these mutations. Three novel mutations were identified in seven unrelated AJ patients with MSUD. On the basis of genotyping data suggestive of a conserved haplotype at tightly linked markers on chromosome 6q14, the BCKDHB gene encoding the E1β subunit was sequenced. We noted that a large proportion (10 of 34) of families with MSUD that were followed in our clinic were of Ashkenazi Jewish (AJ) descent, leading us to search for a common mutation within this group. Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid metabolism.
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